Neural activity signaling the initiation and termination of action sequences emerges in nigrostriatal circuits during sequence learning We investigated simultaneous changes in behavioral microstructure and neural activity in nigrostriatal circuits as mice learned a self-paced operant task in which eight lever presses would earn a reward. The average lever press rate increased with training, while the behavior of the mice became organized into discrete sequences of about eight presses. As training progressed there was faster performance of more accurate sequences and less behavioral variability, suggesting that a robust action sequence structure emerged with training. We recorded neural activity in nigrostriatal circuits with electrode arrays in the dorsal striatum (DS) and substantia nigra (SN) during the emergence of action sequences. Many medium spiny neurons (MSNs) displayed increased firing rate preceding the first press in a series, which was higher than the rate increase preceding other presses. Sequence initiation specific activity was also found in putative SN GABAergic and dopaminergic neurons. Neurons in all three areas showed modulated activity selectively before the final press of a sequence. Few neurons signaled both sequence initiation and termination. The proportion of neurons showing start/stop related activity was much higher than that showing activity selectively related to middle presses within a sequence. The proportion of press-related neurons did not change during training, but the percentage of neurons with sequence start/stop related neural activity increased with learning. We next attempted to disrupt striatal circuit function using mice with a striatal-specific deletion of NMDAR1 (striatal NR1-KO). Behavior and striatal neuronal activity was examined after 6 days of training on the FR8 schedule in KO mice and littermate controls. Striatal NR1-KO mice learned to lever press for reward, although KOs showed larger inter-sequence-interval (ISI) but not inter-press interval. The proportion of MSNs displaying lever press-related activity was similar in striatal NR1-KO mice and littermate controls, and this proportion did not change with training. However, the percentage of neurons with start/stop activity was decreased in striatal NR1-KO mice compared to controls, and this did not change with training in the KO mice. Striatal NR1-KO mice exhibited little evidence of sequence learning compared with controls. The sequence length after training was different from eight presses in striatal NR1-KO. The impairment in sequence learning did not stem from any obvious motor impairment in striatal NR1-KO mice, as within-sequence press rate was similar between KOs and controls, and the ISI decreased with training in KO mice. Importantly, the variability of sequence behavior for each animal was generally higher in KO and did not diminish as much with training as in controls. In summary, neurons in nigrostriatal circuits can signal the boundaries of self-paced action sequences. This sequence boundary selective neural activity emerges during training to perform a specific action sequence. Striatal-specific loss of NMDA receptors selectively impairs sequence learning, indicating that striatal circuits are necessary to learn and crystallize specific action sequences. Dissociable roles of DA on striatal firing rate and synchrony during akinesia The basal ganglia and DA are involved in action selection and movement initiation. Loss of SN DA projections and decreased striatal DA levels are the characteristic features of Parkinsons disease (PD). Decreased DA levels lead to changes in striatal neuron firing rate, and it is generally believed that DA depletion increases activity in the indirect pathway MSNs (striatopallidal MSNs, expressing mainly D2 receptors) and decreased activity of direct pathway MSNs (striatonigral MSNs, expressing mainly D1 receptors), ultimately resulting in decreased motor cortex activity. However, several recent studies failed to observe decreased overall firing rate in motor cortex after DA depletion. DA loss can result in abnormal oscillatory activity and increased synchrony in the basal ganglia, possibly contributing to Parkinsonian motor deficits. Although DA depletion changes both firing rate and synchrony in striatum, it is not known if these changes are mechanistically related. It is also not known if D1 or D2 type DA receptors have similar effects on rate and synchrony. There may also be more interactions between the direct and indirect pathways than initially thought. It is therefore important to investigate if changes in firing rate and synchrony upon DA disruption are related. Acute blockade of DA receptors (D1, D2, and D1+D2) produced altered the firing rate of striatal neurons, with the majority of neurons showing changes after D1+D2 antagonism. Blockade of D2 type receptors alone also caused a significant proportion of neurons to change firing rate, while blockade of D1-type receptors did not. D1+D2 blockade decreased firing rate in the majority of neurons, and similar effects were observed with blockade of either receptor alone. Thus, the difference in the number of neurons changing rate after D1 or D2 blockade cannot be attributed to differences in the sign of the changes. These data suggest that D2 blockade produces similar changes in neuronal firing rate in the dorsal striatum to those caused by D1+D2 blockade, while blockade of D1-receptors produces smaller changes. D1 blockade produces rate changes similar to those produced by D2 blockade, but in a smaller population of neurons. Acute DA-blockade also changed the entrainment of MSNs to local field potential (LFP) oscillations. Entrainment was low in the baseline condition, but increased after D1+D2 blockade or D1 blockade, while D2 blockade had no such effect. Interestingly, MSNs showing entrainment to the LFP tended to fire near the trough of the LFP oscillation after DA-blockade, corresponding to the point of highest intracellular depolarization. In contrast, fast-spiking interneurons fired preferentially at the peak of the LFP, when intracellular potentials should be more hyperpolarized, while putative cholinergic interneurons tended to fire after the trough of the LFP oscillation. These data confirm that acute D1+D2 blockade leads to increased entrainment of striatal MSNs to the LFP as observed after DA depletion. The effects of the different dopaminergic manipulations suggest that the influences DA signaling on striatal firing rate and synchrony are dissociable. However, this evidence is indirect and based solely on the different magnitudes of the effects of D1 and D2 blockade. We thus determined if there was any relation between the probability of a neuron changing firing rate and changing entrainment to the LFP after DA-blockade. No differences were found in the probability of an entrainment change between rate-changing neurons and non-rate-changing neurons, indicating no consistent relationship between firing rate and entrainment changes after DA-blockade. We conclude: 1) the majority of MSNs show decreased firing frequency, 2) the relative power of the LFP oscillations changes in striatum, and 3) MSNs are entrained to the LFP after acute DA-blockade. Although blockade of D1 or D2 receptors alone produced similar akinesia, the effects of D1 or D2 antagonism on striatal firing rate and synchrony were different. D2 blockade altered MSN firing rate and LFP oscillation power, but did not affect synchrony, while D1 blockade strongly altered synchrony. There was no consistent relationship between firing rate changes and LFP entrainment changes after DA-blockade. Thus, lack of D1 and D2 type receptor activation can exert independent yet interactive effects, which may contribute to PD.